EP1198223A2 - Ophthalmic composition comprising ketotifen - Google Patents

Ophthalmic composition comprising ketotifen

Info

Publication number
EP1198223A2
EP1198223A2 EP00953080A EP00953080A EP1198223A2 EP 1198223 A2 EP1198223 A2 EP 1198223A2 EP 00953080 A EP00953080 A EP 00953080A EP 00953080 A EP00953080 A EP 00953080A EP 1198223 A2 EP1198223 A2 EP 1198223A2
Authority
EP
European Patent Office
Prior art keywords
composition
ketotifen
glycerol
concentration
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00953080A
Other languages
German (de)
French (fr)
Inventor
Marcia Johanna Adam
Andrea Fetz
György Lajos KIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Erfindungen Verwaltungs GmbH, Novartis AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Priority to EP00953080A priority Critical patent/EP1198223A2/en
Publication of EP1198223A2 publication Critical patent/EP1198223A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics

Definitions

  • This invention is directed to an ophthalmic composition comprising ketotifen as a pharmaceutically active agent.
  • compositions comprising ketotifen fumarate are already known, and already on the market.
  • the composition of the present invention is superior compared to the known compositions in that it has a substantially lower dosage of the pharmaceutically active agent.
  • said composition combines a high efficacy with a better tolerability.
  • a further surprising advantage of the composition as disclosed herein is seen in the fact that said composition can be sterilized without any significant decomposition of the pharmaceutically active agent, or other components of the composition.
  • the composition of the present invention comprises a ketotifen salt, in a concentration of 0.01 to 0.04 %, a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, optionally a preservative, acid or base for bringing the pH to weak acidity, and water.
  • the ketotifen salt is preferably ketotifen fumarate.
  • the concentration of the ketotifen salt is preferably 0.03 to 0.04 %, even more preferred 0.025 %.
  • the non-ionic tonicity agent is preferably glycerol.
  • the non-ionic tonicity agent is preferably present in an amount such that the total tonicity of the composition has an osmolarity in the range of 230 to 260 milliosmoles, more preferred to 235 to 255 milliosmoles. If glycerol is used, the concentration of glycerol is preferably in the range of 1.5 to 2.5 %.
  • a preservative is present for multi-dose units, but it is routinely not present in single dose units.
  • the preferred preservative is benzalkonium chloride.
  • the amount of the preservative is 0.005 to 0.02 %, more preferred 0.01 %.
  • An acid or base is used in small amounts, such as 0.05 to 0.1 %, for adjusting the pH, preferred is the use of small amounts of sodium hydroxide 1 N, e.g. 0.075 % of such solution.
  • the pH of the composition is adjusted to weak acidity for optimization of stability and tolerabilty, and said pH of weak acidity is understood to mean preferably a pH of 4.4 to 5.8, more preferably a pH of 5 to 5.5, and most preferably a pH of 5.3.
  • the water present in the composition is typically water for injection.
  • a preferred composition of this invention comprises ketotifen fumarate, in a concentration of 0.03 to 0.04 %, glycerol in a concentration of 2 to 2.5 %, optionally benzalkonium chloride in an amount of 0.005 to 0.02 %, sodium hydroxide, and water.
  • An even more preferred composition comprises ketotifen fumarate, in a concentration of 0.025 %, glycerol in a concentration of 2.125 %, optionally benzalkonium chloride in an amount of 0.01 %, sodium hydroxide, and water.
  • the ophthalmic composition of this invention is useful as eye drops, whether as a preserved multi dose unit, or as an unpreserved single dose unit.
  • Said eye drops do have a high therapeutic value because they can be used for the treatment and the temporary prevention of itching of the eye due to allergic conjunctivitis, and they can be used for the treatment and prevention of signs and symptoms of seasonal allergic conjunctivitis.
  • ketotifen fumarate Despite the low concentration of the pharmaceutically active ingredient, ketotifen fumarate, the recommended dosage is lower than for known ketotifen fumarate preparations. Thus, one drop of the composition of this invention should be applied advantageously two times per day, in contrast to 1 to 2 drops four times a day of the prior art compositions.
  • the fact that the composition of this invention can be applied with an overall very low level of pharmaceutically active ingredient, especially ketotifen fumarate, is one of the surprising findings in the context of this invention. A further finding is that a stabilizer such as for example sodium edetate might be omitted.
  • Said ophthalmic composition can be manufactured by mixing the ingredients, and packaging the resulting mixture, both as known in the art. Sterilization of the composition and the primary package can be effected e.g. by gamma irradiation, by ethyleneoxide treatment, by electron beam, by autoclaving or by steam sterilization.
  • Ketotifen fumarate 0.25 mg (0.025 %)
  • Ketotifen fumarate 0.25 mg (0.025 %)

Abstract

The present invention is related to an ophthalmic composition comprising ketotifen as a pharmaceutically active agent.

Description

Ophthalmic Composition
This invention is directed to an ophthalmic composition comprising ketotifen as a pharmaceutically active agent.
An ophthalmic composition comprising ketotifen fumarate is already known, and already on the market. The composition of the present invention is superior compared to the known compositions in that it has a substantially lower dosage of the pharmaceutically active agent. In result said composition combines a high efficacy with a better tolerability. A further surprising advantage of the composition as disclosed herein is seen in the fact that said composition can be sterilized without any significant decomposition of the pharmaceutically active agent, or other components of the composition.
The composition of the present invention comprises a ketotifen salt, in a concentration of 0.01 to 0.04 %, a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, optionally a preservative, acid or base for bringing the pH to weak acidity, and water.
The ketotifen salt is preferably ketotifen fumarate. The concentration of the ketotifen salt is preferably 0.03 to 0.04 %, even more preferred 0.025 %. The non-ionic tonicity agent is preferably glycerol. The non-ionic tonicity agent is preferably present in an amount such that the total tonicity of the composition has an osmolarity in the range of 230 to 260 milliosmoles, more preferred to 235 to 255 milliosmoles. If glycerol is used, the concentration of glycerol is preferably in the range of 1.5 to 2.5 %. A preservative is present for multi-dose units, but it is routinely not present in single dose units. If a preservative is present, the preferred preservative is benzalkonium chloride. Typically the amount of the preservative is 0.005 to 0.02 %, more preferred 0.01 %. An acid or base is used in small amounts, such as 0.05 to 0.1 %, for adjusting the pH, preferred is the use of small amounts of sodium hydroxide 1 N, e.g. 0.075 % of such solution. The pH of the composition is adjusted to weak acidity for optimization of stability and tolerabilty, and said pH of weak acidity is understood to mean preferably a pH of 4.4 to 5.8, more preferably a pH of 5 to 5.5, and most preferably a pH of 5.3. The water present in the composition is typically water for injection. A preferred composition of this invention comprises ketotifen fumarate, in a concentration of 0.03 to 0.04 %, glycerol in a concentration of 2 to 2.5 %, optionally benzalkonium chloride in an amount of 0.005 to 0.02 %, sodium hydroxide, and water. An even more preferred composition comprises ketotifen fumarate, in a concentration of 0.025 %, glycerol in a concentration of 2.125 %, optionally benzalkonium chloride in an amount of 0.01 %, sodium hydroxide, and water.
The ophthalmic composition of this invention is useful as eye drops, whether as a preserved multi dose unit, or as an unpreserved single dose unit. Said eye drops do have a high therapeutic value because they can be used for the treatment and the temporary prevention of itching of the eye due to allergic conjunctivitis, and they can be used for the treatment and prevention of signs and symptoms of seasonal allergic conjunctivitis.
Despite the low concentration of the pharmaceutically active ingredient, ketotifen fumarate, the recommended dosage is lower than for known ketotifen fumarate preparations. Thus, one drop of the composition of this invention should be applied advantageously two times per day, in contrast to 1 to 2 drops four times a day of the prior art compositions. The fact that the composition of this invention can be applied with an overall very low level of pharmaceutically active ingredient, especially ketotifen fumarate, is one of the surprising findings in the context of this invention. A further finding is that a stabilizer such as for example sodium edetate might be omitted.
Said ophthalmic composition can be manufactured by mixing the ingredients, and packaging the resulting mixture, both as known in the art. Sterilization of the composition and the primary package can be effected e.g. by gamma irradiation, by ethyleneoxide treatment, by electron beam, by autoclaving or by steam sterilization.
Example 1 : Multidose Units:
Ketotifen fumarate 0.25 mg (0.025 %)
Benzalkonium chloride 0.10 mg (0.010 %)
Glycerol 100 % 21.25 mg (2.125 %)
Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %)
Water for injection ad ad 1.0 ml Example 2: Single dose Units:
Ketotifen fumarate 0.25 mg (0.025 %)
Glycerol 100 % 21.25 mg (2.125 %)
Sodium hydroxide 1 N about 0.75 mg (- 0.075 %)
Water for injection ad ad 1.0 ml

Claims

Claims
1. An ophthalmic composition comprising a ketotifen salt, in a concentration of 0.01 to 0.04 %, a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, optionally a preservative, acid or base for bringing the pH to weak acidity, and water.
2. The composition of claim 1 wherein the ketotifen salt is ketotifen fumarate.
3. The composition of claim 1 wherein the concentration of the ketotifen salt is 0.03 to 0.04 %, preferably 0.025 %.
4. The composition of claim 1 wherein the non-ionic tonicity agent is glycerol.
5. The composition of claim 1 wherein the non-ionic tonicity agent is glycerol in an amount of 1.5 to 2.5 %.
6. The composition of claim 1 wherein the preservative is benzalkonium chloride.
7. The composition of claim 1 wherein the preservative is absent.
8. The composition of claim 1 which comprises ketotifen fumarate, in a concentration of 0.03 to 0.04 %, glycerol in a concentration of 2 to 2.5 %, optionally benzalkonium chloride in an amount of 0.005 to 0.02 %, sodium hydroxide, and water.
9. The composition of claim 1 which comprises
Ketotifen fumarate 0.25 mg (0.025 %),
Benzalkonium chloride 0.10 mg (0.010 %),
Glycerol 100 % 21.25 mg (2.125 %),
Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %),
Water for injection ad ad 1.0 ml.
10. The composition of claim 1 which comprises Ketotifen fumarate 0.25 mg (0.025 %),
Glycerol 100 % 21.25 mg (2.125 %),
Sodium hydroxide 1 N about 0.75 mg (~ 0.075 %),
Water for injection ad ad 1.0 ml.
EP00953080A 1999-07-23 2000-07-21 Ophthalmic composition comprising ketotifen Withdrawn EP1198223A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00953080A EP1198223A2 (en) 1999-07-23 2000-07-21 Ophthalmic composition comprising ketotifen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99114508 1999-07-23
EP99114508 1999-07-23
PCT/EP2000/007030 WO2001007049A2 (en) 1999-07-23 2000-07-21 Ophthalmic composition comprising ketotifen
EP00953080A EP1198223A2 (en) 1999-07-23 2000-07-21 Ophthalmic composition comprising ketotifen

Publications (1)

Publication Number Publication Date
EP1198223A2 true EP1198223A2 (en) 2002-04-24

Family

ID=8238654

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00953080A Withdrawn EP1198223A2 (en) 1999-07-23 2000-07-21 Ophthalmic composition comprising ketotifen

Country Status (20)

Country Link
US (2) US6777429B1 (en)
EP (1) EP1198223A2 (en)
JP (1) JP2003505419A (en)
KR (1) KR20020012261A (en)
CN (1) CN1358086A (en)
BR (2) BR0012696A (en)
CA (1) CA2377024A1 (en)
CZ (1) CZ300614B6 (en)
EE (1) EE05439B1 (en)
HK (1) HK1046631A1 (en)
HU (1) HU230738B1 (en)
IL (1) IL146973A0 (en)
MX (1) MXPA02000849A (en)
NO (1) NO331228B1 (en)
NZ (1) NZ516108A (en)
PL (1) PL202496B1 (en)
RU (1) RU2248789C2 (en)
UA (1) UA74788C2 (en)
WO (1) WO2001007049A2 (en)
ZA (1) ZA200200425B (en)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR034372A1 (en) * 2001-06-08 2004-02-18 Novartis Ag PHARMACEUTICAL COMPOSITIONS
WO2002100436A2 (en) * 2001-06-08 2002-12-19 Novartis Ag Ophthalmic once-a-day composition
AR034371A1 (en) * 2001-06-08 2004-02-18 Novartis Ag PHARMACEUTICAL COMPOSITIONS
KR20120035220A (en) * 2003-01-22 2012-04-13 센주 세이야꾸 가부시키가이샤 Percutaneous absorption preparation for treating ophthalmic disease, use thereof and method for migration of ophthalmic remedy into topical tissue in eye
US20060089384A1 (en) * 2004-10-25 2006-04-27 Minno George E Ophthalmic compositions and methods of using the same
CN101087607B (en) * 2004-10-25 2010-07-28 博士伦公司 Ophthalmic compositions and methods of using the same
US20070208058A1 (en) * 2004-10-25 2007-09-06 Bryant Roy W Stable Pharmaceutical Compositions and Methods of Making and Using Same
US20070048389A1 (en) * 2005-08-26 2007-03-01 Fu-Pao Tsao Stabilized and preserved ketotifen ophthalmic compositions
US20070077302A1 (en) * 2005-09-30 2007-04-05 Azaam Alli Methods for stabilizing ophthalmic compositions
US7608261B2 (en) 2006-06-16 2009-10-27 Regeneron Pharmacuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration
US8445437B2 (en) * 2006-07-27 2013-05-21 The Brigham And Women's Hospital, Inc. Treatment and prevention of cardiovascular disease using mast cell stabilizers
JP5758074B2 (en) 2006-09-29 2015-08-05 ジョンソン・アンド・ジョンソン・ビジョン・ケア・インコーポレイテッド Methods and ophthalmic devices used for the treatment of eye allergies
US20100166804A1 (en) * 2007-05-23 2010-07-01 Dennis Penn Methods
WO2009045291A2 (en) * 2007-09-28 2009-04-09 The Brigham And Women's Hospital, Inc. Mast cell stabilizers in the treatment of obesity
WO2009142772A2 (en) 2008-05-23 2009-11-26 Mastcell Pharmaceuticals, Inc. Methods and treatment for allergies and inflammation associated with gastrointestinal diseases
WO2010107525A1 (en) * 2009-03-17 2010-09-23 Aciex Therapeutics, Inc. Ophthalmic formulations of ketotifen and methods of use
RU2549472C1 (en) * 2013-12-26 2015-04-27 Илья Александрович Марков Pharmaceutical composition in form of eye drops for preventing and treating allergic eye diseases
EP3384049B1 (en) 2015-12-03 2023-08-02 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-vegf
CN111450051B (en) * 2020-04-21 2022-03-18 武汉贝参药业股份有限公司 Preparation method of ketotifen fumarate oral solution

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62277323A (en) 1986-02-19 1987-12-02 Sankyo Co Ltd Production of eye drop containing ketotifen fumarate
JPH07324034A (en) * 1994-05-30 1995-12-12 Toa Yakuhin Kk Eye drop containing ketotifen fumarate
JPH11189533A (en) * 1997-12-25 1999-07-13 Taisho Pharmaceut Co Ltd Eye drop
EP0938896A1 (en) 1998-01-15 1999-09-01 Novartis AG Autoclavable pharmaceutical compositions containing a chelating agent

Non-Patent Citations (1)

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Also Published As

Publication number Publication date
CN1358086A (en) 2002-07-10
CZ300614B6 (en) 2009-07-01
CA2377024A1 (en) 2001-02-01
HU230738B1 (en) 2018-01-29
BRPI0017528A2 (en) 2010-01-19
PL352382A1 (en) 2003-08-25
NO20020319D0 (en) 2002-01-21
HUP0202243A2 (en) 2002-12-28
WO2001007049A3 (en) 2001-03-29
PL202496B1 (en) 2009-06-30
US6774137B2 (en) 2004-08-10
BR0012696A (en) 2002-04-09
KR20020012261A (en) 2002-02-15
EE05439B1 (en) 2011-08-15
MXPA02000849A (en) 2002-07-30
WO2001007049A2 (en) 2001-02-01
US20020183359A1 (en) 2002-12-05
BRPI0017528B8 (en) 2021-05-25
IL146973A0 (en) 2002-08-14
HUP0202243A3 (en) 2006-03-28
UA74788C2 (en) 2006-02-15
BRPI0017528B1 (en) 2017-06-13
NO331228B1 (en) 2011-11-07
RU2248789C2 (en) 2005-03-27
US6777429B1 (en) 2004-08-17
ZA200200425B (en) 2002-10-30
NZ516108A (en) 2004-04-30
CZ2002243A3 (en) 2002-04-17
HK1046631A1 (en) 2003-01-24
NO20020319L (en) 2002-01-21
JP2003505419A (en) 2003-02-12
EE200200040A (en) 2003-04-15

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